Clinical impact of the right ventricular impairment in patients following transcatheter aortic valve replacement

The right ventricular (RV) impairment can predict clinical adverse events in patients following transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). Limited reports have compared impact of the left ventricular (LV) and RV disorders. This retrospective study evaluated two-year major adverse cardiac and cerebrovascular events (MACCE) in patients following TAVR for severe AS. RV sphericity index was calculated as the ratio between RV mid-ventricular and longitudinal diameters during the end-diastolic phase. Of 239 patients, 2-year MACCE were observed in 34 (14%). LV ejection fraction was 58 ± 11%. Tricuspid annular plane systolic excursion (TAPSE) and RV sphericity index were 20 ± 3 mm and 0.36 (0.31–0.39). Although the univariate Cox regression analysis demonstrated that both LV and RV parameters predicted the outcomes, LV parameters no longer predicted them after adjustment. Lower TAPSE (adjusted hazard ratio per 1 mm, 0.84; 95% confidence interval, 0.75–0.93) and higher RV sphericity index (adjusted hazard ratio per 0.1, 1.94; 95% confidence interval, 1.17–3.22) were adverse clinical predictors. In conclusion, the RV structural and functional disorders predict two-year MACCE, whereas the LV parameters do not. Impact of LV impairment can be attenuated after development of RV disorders.

Transcatherter aortic valve replacement (TAVR) has been emerged as alternative therapy for patients with severe aortic stenosis (AS) at high or prohibitive surgical risk 1 and can provide better prognosis in such population.However, even after the procedure, major adverse cardiac and cerebrovascular events (MACCE) such as heart failure hospitalization may occur and result in impaired activity daily living, higher cost, higher incidences of mortality and morbidities 2 .It would be necessary to identify patients at a risk of clinical adverse events after TAVR for suppression of cost and improvement in prognosis.
According to current guidelines, surgical or transcatheter aortic valve replacement (AVR) is determined based on the demonstration of severe AS, presence or absence of symptoms related to AS, and left ventricular ejection fraction (LVEF) 3 .The AVR decision algorithm does not include cardiac structural and functional findings other than LVEF.Of cardiac impairment, the right heart structure and function, which have been largely underestimated in the left heart diseases 4 , have attracted attention of clinicians and researchers for the last few years.Indeed, both structural and functional impairment of the right heart predicted worse clinical outcomes in patients who underwent TAVR according to some recent studies [5][6][7][8] .The conception of staging classification based on the extra-aortic valve cardiac damage supports the importance of the right heart findings 9 and may suggest that the right ventricular (RV) dysfunction reflects the advanced left ventricular (LV) dysfunction 10 .It should be clarified which, or both of the LV and RV characteristics is important to predict adverse clinical events.Understanding of any interactions between the LV and RV (or the left and right heart system) disorders may contribute to better patient selection for TAVR.
The present study aimed to (1) identify predictors related to the RV structure and function, (2) demonstrate whether the RV dysfunction may predict adverse clinical outcomes more accurately than that of the LV, and (3) investigate which LV parameters are associated with the RV findings in patients who underwent TAVR for severe AS.

Echocardiographic findings
Echocardiography was conducted and analyzed by experienced cardiologists or clinical technologists.All patients underwent transthoracic echocardiography prior to TAVR.Severity of AS was determined based on the max velocity, mean pressure gradient, or AV area according to the ACC/AHA guideline 3 .LVEF, left ventricular enddiastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV) were assessed by using modified Simpson's biplane method.The right ventricular (RV) and atrial size and the diameter of the inferior vena cava were measured.RV sphericity index was calculated as the ratio between RV mid-ventricular and longitudinal diameters during the end-diastolic phase (Fig. 1) 12 , which is an indicator of RV remodeling 13 .LV sphericity index was also determined using same method as the RV sphericity index.Tricuspid annulus diameter was also measured during the end-diastolic phase.Systolic right ventricular function was assessed by TAPSE and RV fractional area change.Systolic pulmonary artery pressure (SPAP) was determined by measurement of the maximal tricuspid regurgitation velocity-derived gradient by continuous wave Doppler, inferior vena cava diameter, and respiratory-related changes in inferior vena cava diameter 14 .RV-PA coupling, which represents the association between the right ventricular contractility and pulmonary afterload, was defined as TAPSE-to-SPAP ratio (mm/ mm Hg).Severity of mitral regurgitation (MR) and tricuspid regurgitation (TR) was scored on a scale ranging from 1 + (mild) to 4 + (severe) 15 and 1 + (mild) to 5 + (torrential) 16 , respectively.None or trivial regurgitation was categorized as 0. MR and TR vena contracta (VC) were evaluated during the mid-systolic phase.

Definitions
Reduced LVEF was defined as LVEF less than 40%.Pulmonary hypertension (PH) was determined if SPAP was 38 mmHg or higher according to transthoracic echocardiography 17 .Chronic kidney disease (CKD) stages 3B-5 was diagnosed based on an estimated glomerular filtration rate < 45 ml/min/1.73m 218 .Baseline laboratory evaluation of hepatobiliary function included total bilirubin (TB), alkaline phosphatase (ALP), and GGT.TB was considered abnormal if it exceeded 1.2 mg/dL, irrespective of sex.For ALP and GGT, we used sex-specific laboratory cutoff values as follows: ALP, 130 U/L (males) and 105 U/L (females); gamma glutamyl transferase (GGT), 59 U/L (males) and 39 U/L (females).Hepatobiliary system impairment was defined as elevation of at least two of three parameters (TB, ALP, and GGT) 19 .

Ethical statement
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.This study was approved by the Ethics Committee of our University on 11th July 2022 (the approval number: 22-087-B).The study satisfied the conditions needed to waive the requirement for written informed consent from the study participants.The ethics committee approved this waiver.

Statistical analysis
Continuous variables are described as mean ± standard deviation if the skewness-kurtosis test did not reject the hypothesis of normality.Otherwise, variables are presented as medians with interquartile range values.Categorical variables are displayed as absolute numbers and percentages.Continuous variables were assessed using unpaired Student's t tests or Mann-Whitney U tests, whereas Fisher's exact test or the chi-squared test was used for categorical variables, as appropriate.Each cutoff value of TAPSE or RV sphericity index was determined based on the Liu index.The intra-and inter-observer reproducibility for the RV sphericity index were assessed through Bland-Altman analysis in thirty-four patients, respectively.Before the analysis, the skewness-kurtosis test was conducted to confirm whether the differences followed a normal distribution.When the RV sphericity index measured by X and Y, 100 (X-Y)/mean (X, Y) is plotted on the y-axis, mean (X, Y) on the x-axis.The risk of two-year MACCE was evaluated using Cox regression analysis and expressed as hazard ratio (HR) with 95% confidence interval (CI).The follow-up began on the day of TAVR.The follow-up was completed two years after the procedure or the date when the end-point events were observed, depending on what happened first.Multivariate Cox regression analysis was conducted using forward-backward stepwise selection.Variables with a p value < 0.25 in the univariate Cox regression analysis were selected for the multivariate Cox regression analysis.A minimum of five outcome events per predictor variable was applied to the construction of multivariate models 23 .The nonparametric bootstrap method, resampling with replacement 1000 times, was conducted to provide inner validation.Statistical significance was defined as a p value < 0.05.All statistical analyses were performed using Stata version 14 (StataCorp, College Station, TX, USA).
Cutoff values ant the C-statistics of TAPSE and RV sphericity index were 19 mm (0.65 [0.56-0.74])and 0.377 (0.60 [0.49-0.71]),respectively.Patients with at least an impaired RV parameters underwent a higher incidence of two-year MACCE compared to those without such disorders (Fig. 3).RA area, SPAP, and TR severity were not correlated with the clinical adverse events.It is noteworthy that RV-PA coupling did not predict the worse outcomes.

Association between the left and right heart structure and function
There was a significant difference of TAPSE between patients with and without reduced LVEF (p = 0.001) (Fig. 4A).PH was not associated with a value of TAPSE (p = 0.624).On the other hand, PH was significantly related to higher RV sphericity index (p = 0.039) (Fig. 4B) and reduced LVEF was not (p = 0.224).Larger tricuspid annulus diameters and RA areas were observed in patients with PH (p = 0.002 and p < 0.001, respectively).Association of reduced LVEF with such parameters was not observed (p = 0.642 and p = 0.211, respectively).

Reproducibility of the RV sphericity index
The intra-and inter-observer differences were − 0.01 ± 0.04 and − 0.02 ± 0.07, both of which followed a normal distribution according to the skewness-kurtosis test (p = 0.115 and p = 0.468, respectively).Figure 5 demonstrates good intra-and inter-observer agreement.

Discussion
The current study demonstrated that RV structural and functional parameters such as RV sphericity index and TAPSE predicted the subsequent MACCE, whereas those of LV did not.Further, a lower value of TAPSE was associated with reduced LVEF and a higher value of RV sphericity index was correlated with PH.Noncardiac comorbidities such as impaired kidney function and hepatobiliary system impairment were also clinical adverse predictors.Although severe AS is the most common left-sided valve lesion, its prognosis can be determined by  other lesions.Considering that the RV dysfunction could be a result of advanced LV dysfunction 10 , early intervention may be needed before progression of advanced heart failure.
Although the RV has been recently regarded as an important predictor in cardiovascular diseases, there are few investigations evaluating RV structural characteristics, probably due to the complexity.The LV has an ellipsoid-shaped chamber surrounded by relatively thick musculature, whereas the RV has a crescent-shaped chamber with a thin wall 24 .Further, multiple interactions between the LV and RV make the interpretation of the RV structural findings much more challenging 25 .The unique features make accurate assessment of RV structure difficult; however, some parts of the RV such as shape and tricuspid annulus diameter may reflect its structural disorder to some extent.A previous single-center study refereed to CT-determined tricuspid annulus as a useful predictor 5 .Our study evaluated RV sphericity index as well as tricuspid annulus diameter as a marker of an abnormal RV structure.Consequently, only the former predicted the adverse clinical events.This result would make sense because RV sphericity index evaluates both RV longitudinal and transverse diameters, whereas tricuspid annulus diameter reflects a transverse diameter.RV sphericity index might reflect RV remodeling considering that PH was associated with higher RV sphericity index.Association between TAPSE and LV systolic function has been reported previously 26 .RV dysfunction may be a direct result of LV impairment 27 , which could be mediated by the largely septum, but also by LV free wall 28 .On the other hand, RV dysfunction can also impair LV function by attenuating LV preload and adversely affecting the systolic and diastolic interaction via the intraventricular septum and the pericardium 26 .The potential bidirectional influences mentioned above can help explain why the LV has a lesser impact on two-year MACCE compared to the RV.The clinical impact of the LV features was attenuated in patients with advanced heart failure 14 .
The results of our study recommend assessment of RV characteristics for a risk stratification.The current study evaluated RV features based on 2-dimensional (2D) images, which may be less accurate than 3-dimensional (3D) images.Indeed, a recent study indicated a predictive ability of 3D RV ejection fraction was superior to 2D evaluation such as TAPSE and fractional area change 29 .However, a 3D-image construction of the RV is not available in some cases because of technical difficulty.Cardiovascular magnetic resonance (CMR) can provide 3D RV images easily and more accurate information regarding structure and function compared to echocardiography 30 .It is difficult to apply CMR to all patients scheduled for TAVR in daily clinical practice.Therefore, the RV structure and function should be evaluated by echocardiography at first to identify patients with obviously normal RV structure and function.It may make sense that CMR is applied for patients in whom echocardiography suggests the RV impairment or sufficient evaluation is difficult.
No association of RV-PA coupling with MACCE could be owing to a higher prevalence of heart failure patients.SPAP might become lower after removal of afterload mismatch and pulmonary congestion.According to a previous study, SPAP decreased after the procedure, whereas RV systolic function did not significantly improve 6 .Another previous study indicated that RV-PA coupling prior to TAVR did not predict long-term mortality 31 .
Noncardiac predictors such as hepatobiliary system impairment and renal impairment may be modifiable comorbidities in selective patients.However, considering that SPAP was not associated with the clinical adverse events, modifiable parameters did not predict the outcomes necessarily.It is occasionally difficult to distinguish "true" CKD from cardiorenal syndrome.The same can be said for hepatobiliary system impairment.Future studies dedicated to investigation of such comorbidities would be needed for expanding understanding of prognosis in patients with severe AS.

Figure 1 .
Figure 1.Definition of RV sphericity index.This echocardiographic image in apical four chamber view indicates measurement of RV sphericity index and tricuspid annular diameter.Initially, the tricuspid annulus diameter during the end-diastolic phase was measured (line A).Subsequently, a line was drawn connecting the RV apex to the midpoint of line A (line B).Finally, a perpendicular line was depicted connecting the RV free wall and septum, intersecting the midpoint of line B (line C).The RV sphericity index was calculated as the ratio between line C / line B. RV, right ventricular.

Figure 2 .
Figure 2. Forest plot of the multivariate Cox regression analysis for two-year MACCE.The multivariate Cox regression analysis demonstrated that lower TAPSE, higher RV sphericity index, hepatobiliary system impairment, CKD stages 3B-5, males, and clinical frailty scale of > 4 were associated with higher 2-year MACCE.CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular events; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.

Figure 3 .
Figure 3. Clinical impact of TAPSE and RV sphericity index on 2-year MACCE.The patients were classified into group 1 (TAPSE of ≥ 19 mm and RV sphericity index of < 0.377), group 2 (TAPSE of < 19 mm and RV sphericity of < 0.377), group 3 (TAPSE of ≥ 19 mm and RV sphericity index of ≥ 0.377), and group 4 (TAPSE of < 19 mm and RV sphericity index of < 0.377).Kaplan-Meier survival curve demonstrated that the incidence of MACCE at 2 years differed among the above groups (p = 0.002).Patients with abnormal values of TAPSE and RV sphericity index (group 4) indicated the highest incidence of the outcomes.MACCE, major adverse cardiac and cerebrovascular events; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.

Figure 4 .
Figure 4.A comparison of the LV and RV characteristics.(A) A value of TAPSE was higher in patients with LVEF of ≥ 40%.(B) A value of RV sphericity index was higher in patients with PH.LV, left ventricular; LVEF, left ventricular ejection fraction; PH, pulmonary hypertension; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion.

Figure 5 .
Figure 5. Bland Altman analysis for reproducibility of the RV sphericity index.The blue dashed line indicates the mean and the red dashed lines represent the 95% limits of agreement.(A) The Bland Altman plot depicts good intra-observer agreement.X: The second measurement by S.H. Y: The first measurement by S.H. (B) This figure demonstrates good inter-observer agreement.X: measurement by S.H. Y: measurement by H.M. RV, right ventricular.

impact of the left and right heart structure and function
Two-year MACCE was observed in 34 (14%) and follow-up duration was 556 (220-925) days.Of eligible patients, lost to follow up was observed in 33 patients (14%).Table2discloses the results of univariate Cox regression analysis for two-year MACCE.